Site1 and Site2 Are Structurally and Functionally Coupled

It is likely that this new binding solution for hGHv-hGH-R2 is triggered by a structural mechanism linking site 2 to a subset of the mutations in site 1 introduced in the phage display experiments. It is noteworthy that the structurally distinct conformation of hGHv at site 2 was under no selection pressure and supports binding of the second receptor as tightly as in the wt complex. A specific example of the structural coupling is observed from the altered roles of Asp116 in site 2 of the hormone in the two complexes [43]. Asp116 is located near the center of helix 3, thus the side chain extends off a fairly rigid scaffold. Although Asp116 is adjacent to several important receptor side chains, in the wt complex it appears to play a bystander role, making no H bond

WthCH hGH

WthCH hGH

Figure 3 Comparing the structural changes in site 2 of the hGH and hGHv-hGH-R ternary complexes. Hormone residues are labeled in black and receptor residues in red. Arrows point to the carbonyl oxygen atom of the peptide bond of Trp169 that flips its conformation. The other arrows point to the reorientation of the side chains of Trp169 and Trp104.

Figure 3 Comparing the structural changes in site 2 of the hGH and hGHv-hGH-R ternary complexes. Hormone residues are labeled in black and receptor residues in red. Arrows point to the carbonyl oxygen atom of the peptide bond of Trp169 that flips its conformation. The other arrows point to the reorientation of the side chains of Trp169 and Trp104.

to the receptor. It is probable that the small movements of Asp116 that are a consequence of the repacking of the four-helix bundle in hGHv effectively trigger the new H-bonding scheme where by the carboxylate side chain makes new H bonds to the receptor through the indole nitrogens of the side chains of Trp104 and Trp169, as well as to the side chain of Arg43. As seen in Fig. 3, the Trp side chains undergo a significant reorganization to facilitate the formation of these H bonds. These observations clearly have fundamental importance to our understanding of the inherent efficiencies of these cytokine hormones and receptors as binding entities even outside of evolutionary control.

The concept that the two spatially distinct binding sites on cytokine hormones are structurally and functionally coupled as displayed in the hGHv complex is novel, and the process whereby new binding surfaces are synthesized by indirect through molecule effects has been termed functional cooperativity [43]. In this mechanism, it is not only the mutations in one site that affect the other site. A set of concerted changes also occurs among the hormone and the receptor ECDs. The finding of strong cross-molecular interaction induced during receptor dimerization establishes a new molecular recognition paradigm and opens up fundamental new areas of investigation relating to the mechanisms of biological regulation by protein-protein associations. However, it remains an open question as to how general this is and whether evolution actually uses this strategy to influence the receptor signaling of GH/PRL systems in biologically important ways.

Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook


Post a comment